1. Field of the Invention and Prior Art
The present invention relates to a readily-dispersible physiologically-effective fiber drink mix comprising granules consisting essentially of a blend of a mineral salt which releases a physiologically-acceptable gas upon ingestion, a physiologically-acceptable edible acid, and a gel-forming dietary fiber, which granules are coated with a gel-forming dietary fiber, starch, or protein and which may also advantageously include an orally-ingestible drug or other pharmaceutically-active compound, such as niacin, in said granules.
Guar gum (Cyamopsis Tetragonoloba), a galactomannan polysaccharide, and other gel-forming fibers such as psyllium hydrophilic mucilloid, have been recognized for some time to have a therapeutic value for lowering cholesterol and helping to regulate blood sugar. The cholesterol-lowering properties of guar gum and other mucilaginous substances were initially recognized by Fahrenbach et al. (U.S. Pat. No. 3,148,144).
Guar gum is obtained from a luguminous plant which grows to a height of three to six feet. The Guar plant bears bean-like pods, each of which contains six to nine small rounded seeds. The guar seed is typically composed of 40-46% germ, 38-45% endosperm, and 14-16% husk. Guar gum is used extensively in the food industry and is recognized as safe by the Food and Drug Administration as a food additive.
Guar gum is used in the food industry for various purposes as a food additive. Even at fairly low levels it presents certain problems, such as difficulty of dispersing the guar flour in liquids, or the formation of undissolved lumps or fish eyes of powder, which are effectively sealed from further hydration by a surface gel which prevents further solubility or dispersion.
Jenkins et al. (The Lancet, 1975, 1116 and 1977, 779) discovered that a therapeutic dose of guar gum effective for lowering serum cholesterol or regulating blood sugar required administration of fairly large quantities of guar gum per day. In fact, doses of 15 to 20 grams per day were needed to obtain statistically significant cholesterol reductions.
Stemmle et al. (EPO 0080673) describes many of the problems associated with the use of guar gum in a therapeutic dose. Of the various dosage forms, such as tablets, capsules, and a powder drink mix, problems of solubility, dispersion, hydration, and gelation are all described. With respect to a tablet dosage form, it is widely known that guar gum tablets do not dissolve properly either in vitro or in vivo. The high pressures needed to manufacture tablets compresses the guar flour together and, when these tablets are placed in a gastric simulator or a dissolution apparatus, they do not dissolve. The guar particles on the surface of the tablet hydrate to form an impenetrable gel, effectively sealing off the rest of the tablet, and preventing the dispersion of the guar. After 24 hours in a dissolution apparatus, the tablet still remains undissolved, and sits like a rock at the bottom of the apparatus. Various additives normally used as disintegrants to break up tablets, such as crosslinking or wicking agents or microcrystalline cellulose, do not solve the problem.
Day and Kuhrts (U.S. Pat. No. 4,824,672) teach the use of mineral carbonates to enhance dispersion of guar gum and other gummy fibers.
With respect to powder drink mix dosage forms, similar problems exist. The guar gum is not only extremely difficult to mix and dissolve, but what small amount does hydrate immediately forms a thick gel, which becomes impossible to drink.
Steinitz (U.S. Pat. No. 2,935,408) describes the use of a suspension agent with a gum to overcome some of the problems associated with using gums as stabilizers in the food industry. In this patent, the gum is predispersed in a non-aqueous water-free liquid matrix, thereby to condition it for further dispersal throughout an aqueous carrier. An example of an ideal suspension agent was glyceryl monostearate. This results in a slurry which can be used as a stabilizer to be added to an aqueous solution such as a gravy, salad dressing, toppings, jams, etc. This slurry would not be suitable for a pharmaceutical dosage form.
Jordan (U.S. Pat. No. 3,007,879) teaches the stabilization of guar gum solutions against viscosity change, as well as an improved method of mixing such dispersions, and maintaining a stable high viscosity over a substantial period of time. Organic acids are used to stabilize the guar gum solutions, but only after they have formed a gel.
Jackson, Jr. (U.S. Pat. No. 3,313,800) describes guar gum coprecipitation with gelatin from hydro-alcoholic media. The guar gum is dissolved in the alcohol/water solution and dried. The process is one of precipitation. This further shows that gelation of guar gum is a real problem, and many different solutions to this problem have been attempted.
Applegren (U.S. Pat. No. 4,754,027) describes coating fine particles of guar gum with water:solvent and film-forming fatty acids, film-forming polymers, and ethyl cellulose. Examples of solvents are ethanol, lower ketones such as acetone, benzene, xylene, and toluene. An example is the use of a polymer of dimethylaminoethyl-methacrylate for the film-forming agent and acetone:isopropanol (40:60) as solvent. Among the many drawbacks of his contribution are the use of pollution-causing substances which require special pollution-control devices and subject the manufacture to regulatory control; the expense of the film-forming agents and solvents, making this product very expensive; and failure to provide for a further dispersion of the fine guar particles within the granules, so that, after his film dissolves, the guar still has an impenetrable film of guar gel around the nucleus. In addition, his particle size and the texture of his particles create a gritty texture and an objectionable mouthfeel to the product and his particles have a tendency to sink to the bottom when mixed in a liquid, quite in contrast to the granules of the present invention, which do not have these shortcomings.
Nittner (U.S. Pat. No. 4,675,312) discloses agglomerating a substance such as guar gum with an agglomerating agent such as an animal or vegetable product, so that the guar is metabolized more slowly in the intestines.
Showa Sangyo (J.P. 59175436) involves inhibiting viscosity (gelation) of polysaccharides (e.g., guar gum, etc.), by treating them with high pressure or ultrasonic waves. However, this could destroy the activity of the guar gum by producing a structural change.
Heath (G.B. Patent 2,030,583) forms a granulate of guar gum by agglomeration. This produces particles which will dissolve in water, producing drinkable mixtures. Granules of guar are formed by spraying the powder with atomized water and drying. Particles of 100 to 1000 microns, with a water content of 5 to 25% by weight, are created. These granules are gritty and objectionable to consumers and it has been found that each granule must be 250 microns at a maximum or else they do not dissolve, because the outer layer of the granule gels up and seals off the inner part of the granule, much like what normally occurs with the usual guar gum in tablet or capsule form. Moreover, it is very difficult to control particle growth when spraying guar with just water. It is easier to use a carrier such as carboxymethyl cellulose, as taught herein. In addition, much less water can be used than in the spraying of guar gum particles with water.
U.S. Pat. Nos. 4,790,991, 4,747,881, and 4,818,539 describe coating dietary fibers and drugs with a preswelled hydrocolloid, wherein the substrate (drug or fiber) and the hydrocolloid are not the identical material, and wherein the substrate contains cholestyramine. The hydrocolloids are selected from the group consisting of natural and modified gums, cellulose, modified celluloses, pectin, mucillages, modified starches, etc. U.S. Pat. No. 4,747,881 in particular describes coating locust bean gum with carboxymethylcellulose (Example 1). There is no mention of the use of a mineral carbonate or bicarbonate or an edible acid or of gelatin or a caseinate as coating agents. The particles created tend to form small spheres which have a gel coating around their circumference. The hydrocolloid coating slows down the gelation of the aggregate, but each individual particle does not fully disperse or hydrate when the hydrocolloid layer dissolves and the gastric fluid comes in contact with the core material (substrate). Furthermore, the hydrocolloid is always different than the substrate or core material.
EPO 0007619 discloses the use of gelatin hydrolysates to inhibit the gelation of polysaccharide gums such as guar or locust bean gums. The gelation of the gum is inhibited by admixing or blending it with gelatin and adding an effective quantity of alkalinizer such as sodium glycinate. The preferred ratio of guar gum to gelatin, however, is 0.5:1 (Example 1, EPO 0007619), which means that there is twice as much inhibitor as guar gum. This severely limits the usefulness of that invention because guar gum must be taken in large amounts to be therapeutically effective, and one would be consuming large amounts of gelatin with it. In a daily dose of 15 grams of guar gum, one would also be consuming 30 grams or more of gelatin. This patent teaches that the inhibition of gelation is believed to occur when the polysaccharide gum is first hydrated.
"The surface of the polysaccharide gum particles rapidly hydrate and associate either by hydrogen bonding or by electrostatic forces with the inhibitor, which has dissolved already. The hydrogen bonding between polysaccharide molecules, which would otherwise cause gelation, is impeded by the presence of the inhibitor". PA1 a. Antipyretics and analgesics such as acetaminophen, aspirin and ibuprofen PA1 b. Appetite suppressants such as phenylpropanolamine hydrochloride and stimulants such as caffeine PA1 c. Potassium, KCl, or another mineral supplement PA1 d. Vitamin C PA1 e. Vitamin B-12 PA1 f. Antihypercholesterolemics, and especially Niacin PA1 g. Antitussives, such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, and chlophedianol hydrochloride. PA1 h. Antihistamines, such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, and phenyltoloxamine citrate. PA1 i. Decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, and ephedrine.
The inhibition is reversed when the mixture is consumed and reaches the acid environment of the stomach where there is a pH change. Other protein hydrolysates and carbohydrate derivatives are also mentioned as inhibitors, because they are susceptible to pH change. The formulation also requires an alkalinizer to adjust the pH and insure inhibition of gelation. Nowhere in this patent is mentioned the coating of guar or other gel-forming fibers with gelatin or other protein or with any other substance.
GB 2021948 discloses the coating of gums such as guar gum or locust bean gum with a layer of protein such as soya flour, gluten, or casein having a greater tendency to absorb water than the gum. The gum and the coating substance are mixed in preferably equal amounts with water to produce a dough which is dried and crushed. The resulting composition gels slowly when mixed with water. There is no mention of coating a mixture or granulate of a gel-forming dietary fiber, mineral carbonate or bicarbonate, and an edible acid, with or without a drug, with a protein such as gelatin or sodium caseinate or the like.
The present invention provides a significant improvement over all known previous attempts at producing a gel-forming dietary fiber drink mix by producing a more readily and completely dispersible and more completely bioavailable product. The present invention furthermore provides such a novel delivery system vehicle for the oral consumption of a drug, such as niacin, in a powdered drink mix dosage form. Heretofore, there has not existed a niacin drink mix which can be consumed in liquid beverage form, and which virtually eliminates the unpleasant side effects of niacin such as flushing and itching and having the skin turn bright red. The following Examples illustrate the process and composition of the present invention and will serve to demonstrate the many benefits of the invention. Insofar as the present invention provides a more readily dispersible and more completely dispersible powder drink mix of a gel-forming dietary fiber, such as guar gum or the like, and moreover insofar as it provides such a drink mix which also incorporates an orally-ingestible biologically-absorbable drug or other active pharmaceutical agent, such as niacin, it definitely fulfills a longstanding need in the art.